Type 1 diabetes (T1D) is characterized by loss of functional beta cell mass, but therapies to halt this process are not available. We have discovered thioredoxin-interacting protein (TXNIP), as a promising target in this regard as TXNIP promotes beta cell apoptosis and impairs beta cell function and insulin production, whereas whole body or beta cell-specific TXNIP deficiency protect against multiple low-dose streptozotocin (STZ)- induced diabetes and enhance pancreatic beta cell mass. Interestingly, we have now found that the commonly used anti-hypertensive drug and calcium channel-blocker, verapamil, effectively lowers beta-cell TXNIP expression in rodent beta-cells and human islets, promotes beta-cell survival and rescues mice from T1D. This makes verapamil a potentially attractive drug for T1D, but prospective clinical data are lacking. In addition, we recently discovered a specific novel small molecule TXNIP inhibitor that effectively reduced pro-apoptotic TXNIP in human islets. However, its effects on in vivo TXNIP expression and beta cell mass especially in the context of T1D remain to be elucidated. The overarching hypothesis is that TXNIP inhibition by verapamil and/or novel specific small molecule TXNIP inhibitors will promote functional beta cell mass in T1D. Our Specific Aims are to 1) Study the effects of verapamil and TXNIP inhibition on functional beta cell mass in patients with new-onset T1D by conducting a randomized, placebo-controlled, double-blind clinical trial to assess the feasibility, efficacy and safety of a two-year course of oral verapamil. The primary endpoint will be functional beta cell mass as assessed by mixed meal-stimulated C-peptide; secondary endpoints will include insulin requirements, glycemic control and changes in beta cell biomarkers. 2) Test novel TXNIP inhibitors in models of T1D and human islets. Using mouse models of T1D (STZ and NOD), we will analyze the ability of our newly identified TXNIP inhibitor, TI3, to reduce beta cell TXNIP expression in vivo and reverse or improve loss of beta cell mass and diabetes. We will also use primary human islets to further test TI3 and any additional small molecule TXNIP inhibitors identified in our small molecule screen. 3) Elucidate the molecular mechanism involved in promotion of functional beta cell mass in response to TXNIP inhibitors. We will assess the effects of TI3 and any other TXNIP inhibitor identified on beta cell death/apoptosis, proliferation/regeneration, and insulin production/function in the context of T1D (STZ and NOD mouse models) and in primary human islets exposed to T1D-associated inflammatory cytokines. The results of these studies will have major translational implications with potential immediate clinical impact, provide new insight into beta cell biology and help develop novel therapeutic strategies to increase functional human beta cell mass in vivo and protect residual beta cell mass in T1D.